MC# 16-07 - An Open-Label, Multicenter, Global Phase II Basket Study of Entrectinib for the Treatment of Patients with Locally Advanced or Metastatic Solid Tumors that Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements

  • Agent(s): Entrectinib
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Lymphoma, Melanoma, Mesothelioma, Neuroendocrine, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Thyroid
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): ALK, ROS1, TrkA, TrkB, TrkC

Mechanism of Action

Mechanism of Action: Entrectinib is a potent inhibitor of the tyrosine kinases TrkA, TrkB, TrkC, ROS1 and ALK.  Gene rearrangements in these target kinases are potentially oncogenic drivers.

Purpose

In this study, the sponsor and investigators want to learn:

  • The effects of Entrectinib

  • How much Entrectinib is absorbed into the blood and how fast it is removed

  • If research tests can predict who will benefit from Entrectinib

Inclusion Criteria
  • Histologically- or cytologically-confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3ROS1, or ALK gene rearrangement as determined by Ignyta’s CLIA laboratory or by any nucleic acid-based diagnostic testing method (e.g., NGS, Sanger, RT-PCR, NanoString, EdgeSeq; FISH is not an acceptable method) performed at a local CLIA-certified or equivalently-accredited diagnostic laboratory. (Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest may be eligible provided they meet all other inclusion/exclusion criteria).

  • For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Ignyta’s CLIA laboratory post-enrollment.

  • Measurable disease as assessed locally using RECIST v1.1. (Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the non-measurable disease basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints).

  • Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment. If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide. See Table 3 for a sample list of EIAEDs and non- EIAEDs. Moderate inducers of CYP450, such as dexamethasone or other glucocorticoids, may be used at the discretion of the Investigator. Patients requiring steroids must be at stable or decreasing doses for at least 2 weeks prior to the start of entrectinib treatment.

  • Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements- Note: Prior treatment with crizotinib is permitted in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression).

  • At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of entrectinib treatment.

  • At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of entrectinib treatment.

  • Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment.

  • Age ≥ 18 years.

  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

  • Adequate organ function as defined by the following criteria:
    • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤ 3.0 × upper limit of normal (ULN); ≤ 5.0 × ULN if liver metastases are present

    • Total serum bilirubin ≤ 2.0 × ULN; patients with a known history of Gilbert’s syndrome and/or isolated elevations of indirect bilirubin are eligible

    • Serum creatinine within normal limits or creatinine clearance ≥ 30 mL/min

  • Females of childbearing potential must have a negative serum pregnancy test during Screening and must not be breastfeeding or intending to become pregnant during the study.

  • Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules.

  • Willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

  • Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to the start of entrectinib treatment.

Exclusion Criteria
  • Current participation in another therapeutic clinical trial.

  • Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements. (Note: Prior treatment with crizotinib is permitted in ALK- or ROS1-rearranged NSCLC patients presenting with radiographically-confirmed CNS-only progression).

  • History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy.

  • Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.

  • Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.

  • History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24 hours apart).

  • History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).

  • Peripheral neuropathy Grade ≥ 2.

  • Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including human immunodeficiency virus positive).

  • Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.

  • Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis.

  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT02568267?term=NCT02568267&rank=1

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Re: MC# 16-07